Deep penetration of a PDT drug into tumors by noncovalent drug-gold nanoparticle conjugates

Efficient drug delivery to tumors is of ever-increasing importance. Single-visit diagnosis and treatment sessions are the goal of future theranostics. In this work, a noncovalent PDT cancer drug-gold nanoparticle (Au NP) conjugate system performed a rapid drug release and deep penetration of the drug into tumors within hours. The drug delivery mechanism of the PDT drug through Au NPs into tumors by passive accumulation was investigated via fluorescence imaging, elemental analysis, and histological staining. The pharmacokinetics of the conjugates over a 7-day test period showed rapid drug excretion, as monitored via the fluorescence of the drug in urine. Moreover, the biodistribution of Au NPs in this study period indicated clearance of the NPs from the mice. This study suggests that noncovalent delivery via Au NPs provides an attractive approach for cancer drugs to penetrate deep into the center of tumors.     

Gold nanoparticle-loaded PEGylated dendrimers for <Emphasis Type="Italic">theragnosis</Emphasis>

Both therapy and diagnosis, theragnosis, are indispensable for personalized medicine. Gold nanoparticles (Au NPs) have photochemical properties and attenuate X-rays, which are useful for photothermal therapy and X-ray computed tomography (CT) imaging, respectively. Polyethylene glycol (PEG)-modified dendrimers (PEGylated dendrimers) have been used as drug carriers with prolonged blood circulation. In this study, Au NP-loaded PEGylated dendrimers were prepared as agents for photothermal therapy and CT imaging. Au NPs were grown in the PEGylated dendrimer by adding gold ions and reductants under various conditions to improve the properties. Both size and surface plasmon absorption of the Au NPs increased, dependent on the seeding growth conditions. Au NPs with near infrared absorption were also prepared by seeding growth from Au NP-loaded PEGylated dendrimers using formaldehyde. The Au NPs thus grown showed enhanced photothermogenic properties and CT intensities, enabling efficient photocytotoxicity and the enhancement of the blood pool in mice by CT imaging. Therefore, Au NP-loaded PEGylated dendrimers are a potential agent for theragnosis.     

Prospects of Curcumin Nanoformulations in Cancer Management

There is increasing interest in the use of natural compounds with beneficial pharmacological effects for managing diseases. Curcumin (CUR) is a phytochemical that is reportedly effective against some cancers through its ability to regulate signaling pathways and protein expression in cancer development and progression. Unfortunately, its use is limited due to its hydrophobicity, low bioavailability, chemical instability, photodegradation, and fast metabolism. Nanoparticles (NPs) are drug delivery systems that can increase the bioavailability of hydrophobic drugs and improve drug targeting to cancer cells via different mechanisms and formulation techniques. In this review, we have discussed various CUR-NPs that have been evaluated for their potential use in treating cancers. Formulations reviewed include lipid, gold, zinc oxide, magnetic, polymeric, and silica NPs, as well as micelles, dendrimers, nanogels, cyclodextrin complexes, and liposomes, with an emphasis on their formulation and characteristics. CUR incorporation into the NPs enhanced its pharmaceutical and therapeutic significance with respect to solubility, absorption, bioavailability, stability, plasma half-life, targeted delivery, and anticancer effect. Our review shows that several CUR-NPs have promising anticancer activity; however, clinical reports on them are limited. We believe that clinical trials must be conducted on CUR-NPs to ensure their effective translation into clinical applications.     

A highly efficient and versatile microchip capillary electrophoresis method for DNA separation using gold nanoparticle as a tag

A highly efficient and versatile method for DNA separation using Au nanoparticles (Au NPs) as a tag based on microchip capillary electrophoresis (MCE) was developed. The thiol-modified DNA-binding Au NPs were utilized as a tag. Target DNA was sandwiched between Au NPs and probe DNA labeled with horseradish peroxidase (HRP). In electrophoresis separation, the difference in electrophoretic mobility between free probe and probe-target complex was magnified by Au NPs, which enabled the resulting mixture to be separated with high efficiency by microchip capillary electrophoresis. Horseradish peroxidase was used as a catalytic label to achieve sensitive electrochemical DNA detection via fast catalytic reactions. With this protocol, 27-mer DNA fragments with different sequences were separated with high speed and high resolution. The proposed method was critical to achieve improved DNA separations in hybridization analyses.     

Controlled gold nanoparticle diffusion in nanotubes: Platfom of partial functionalization and gold capping

Multifunctionality of nanotubes (NTs) is essential in biomedical and biotechnological applications, such as drug/gene delivery, bioseparation, and single-molecule detection. Each functionality should be located at optimal positions, depending on their roles such as targeting, tracking, and transporting. This enables avoidance of possible malfunctions or interference caused by having randomly distributed multiple groups (e.g., hydrophobic and hydrophilic) in the same space. In the aspect of multifunctionality, however, a general selective partial functionalization method of NT inner surfaces still remains a challenge. For this reason, we investigated a selective partial functionalization method of NTs using controlled gold nanoparticle (Au NP) diffusion in nanotubes and the preparation method of Au-capped silica nanotubes. Silica nanotubes (SNTs) were prepared using template sol-gel synthesis, and the inside of SNT was selectively modified with (3-trimethoxysilylpropyl) diethylenetriamine (DETA-silane). Au NPs of 2-nm size were then incubated with SNTs with DETA layer inside. Spontaneous diffusion of negatively charged Au NPs from bulk into the positively charged nanochannels of SNTs led trapped Au NPs onto the inner surface of SNTs. The degree of functionalization was controlled by the channel diameter, Au NP concentration, and solvent type. These SNTs partially modified with Au NPs were then used for localized selective chemical functionalization of SNTs. This was accomplished by the reaction between thionylated Au NPs trapped on the inside of SNTs and Alexa555-maleimide. Au-capped SNTs were prepared from SNTs with Au NPs inside by seed-mediated gold growth.     

Pep-1 Peptide-modified liposomal carriers for intracellular delivery of gold nanoparticles

A Pep-1 peptide-modified liposomal (Pep1-Lipo) carrier system was investigated to increase the intracellular delivery of gold nanoparticles (Au NPs). Au NPs with a mean diameter of 13 nm were successfully encapsulated into the inner aqueous compartment of the novel carrier using an ethanol injection technique, reserving the distinctive optical characteristics of the surface plasmon resonance peak around 530 nm. The Au NP-loaded liposomal carrier was physically characterized as 150-170 nm in size and 45 mV in zeta potential. Dark field microscopic observation demonstrated that in vitro cellular association and/or translocation of the nanoprobes into the cells was increased by Pep1-Lipo carriers compared to bare Au NPs. In conclusion, this novel liposomal formulation is a promising platform for the intracellular delivery of metallic nanoprobes including Au NPs.     

Organic Nanoplatforms for Iodinated Contrast Media in CT Imaging

X-ray computed tomography (CT) imaging can produce three-dimensional and high-resolution anatomical images without invasion, which is extremely useful for disease diagnosis in the clinic. However, its applications are still severely limited by the intrinsic drawbacks of contrast media (mainly iodinated water-soluble molecules), such as rapid clearance, serious toxicity, inefficient targetability and poor sensitivity. Due to their high biocompatibility, flexibility in preparation and modification and simplicity for drug loading, organic nanoparticles (NPs), including liposomes, nanoemulsions, micelles, polymersomes, dendrimers, polymer conjugates and polymeric particles, have demonstrated tremendous potential for use in the efficient delivery of iodinated contrast media (ICMs). Herein, we comprehensively summarized the strategies and applications of organic NPs, especially polymer-based NPs, for the delivery of ICMs in CT imaging. We mainly focused on the use of polymeric nanoplatforms to prolong circulation time, reduce toxicity and enhance the targetability of ICMs. The emergence of some new technologies, such as theragnostic NPs and multimodal imaging and their clinical translations, are also discussed.     

On-line enhancement and separation of nanoparticles using capillary electrophoresis

We describe a rapid, simple, and highly efficient capillary electrophoresis (CE)-based method for the analysis of nanoparticles (NPs). In this study, we used the reversed electrode polarity stacking mode (REPSM) of CE to assess the feasibility of enhancing the detection of Au NPs and Au/Ag NPs, optimizing parameters such as the length of time for which the REPSM was applied, the concentrations of the buffer and the sodium dodecylsulfate (SDS) surfactant, and the pH. Under the optimized on-line enhancement conditions [buffer: SDS (40 mM) and 3-cyclohexylamino-1-propanesulfonic acid (CAPS; 10 mM) at pH 10.0; applied voltage: 20 kV; REPSM applied for 24s], the detection limits of the Au NPs and Au/Ag NPs increased by ca. 30- and 140-fold, respectively. In addition, when the NPs were subjected to on-line enhancement and separation by CE using diode array detection (DAD), this approach allowed chemical characterization of the NP species. Our results suggest that such CE analyses will be useful for accelerating the rates of fabrication and characterization of future nanomaterials.     

Retention of enzymatic activity of alpha-amylase in the reductive synthesis of gold nanoparticles

In this paper, we report the generation of Au nanoparticles (NPs), using a pure enzyme for the reduction of AuCl4(-), with the retention of enzymatic activity in the complex. As a model system, alpha-amylase was used to readily synthesize and stabilize Au NPs in aqueous solution. Although several other enzymes were also pursued for the synthesis, it was interesting to observe that only alpha-amylase and EcoRI could produce Au NPs. Following NP synthesis, the activity of the enzyme was retained in the Au NP-alpha-amylase complex. The presence of Au NPs and alpha-amylase in the complex was established by UV-visible and FT-IR spectroscopy, X-ray diffraction (XRD) and transmission electron microscopic (TEM) measurements. Our observations suggest that the presence of free and exposed S-H groups is essential in the reduction of AuCl4(-) to Au NPs. Structural analysis of the enzymes showed that both alpha-amylase and EcoRI enzymes have free and exposed S-H groups in their native form and thus are suitable for the generation of NPs, whereas the other ones used here do not have such groups. Fortuitously, the enzymatic functional group of alpha-amylase is positioned opposite to that of the free and exposed S-H group, which makes it ideal for the production of Au NPs; binding of the enzyme to Au NPs via Au-S bond and also retention of the biological activity of the enzyme.     

Sequential Surface Modification of Au Nanoparticles: From Surface‐Bound AgI Complexes to Ag0 Doping

Gold nanoparticles (Au NPs) with tailor‐made structures and properties are highly desirable for applications in catalysis and sensing. In this context, surface modifications of Au NPs are of particular relevance. Herein, we present a sequential surface modification of Au NPs with Ag^I coordination complexes, which can be converted into Ag⁰‐doped Au NPs by simple ligand‐exchange reaction. The key innovative element of this surface modification is a multifunctional bioxazoline‐based ligand that brings coordinated Ag^I into close proximity to the particle surface.     

Self-assembled cyclodextrin nanoparticles and drug delivery

Drug/cyclodextrin complexes self-assemble in aqueous solutions to form nanosized aggregates or nanoparticles. These complex aggregates are responsible for many of the physicochemical and biological properties of cyclodextrin complexes. Due to the aggregate formation aqueous drug/cyclodextrin solutions can behave more like dispersed nanoscale systems, such as nano-suspensions and liposomes, rather than true solutions. The aggregation can result in enhanced cyclodextrin solubilization of poorly soluble lipophilic drugs; they can serve as building blocks for ternary or higher order complexes; they can be developed into nano- and microparticulated drug carriers for targeted drug delivery to, for example, hair follicles; they can be developed into sustained drug delivery systems; and they can possible be used as mucus-penetrating drug delivery vectors. All of this can be obtained without chemical modifications of the cyclodextrin monomers.     

Multi-compartment containers from a mixture of natural and synthetic lipids

Small anionic liposomes were electrostatically adsorbed on the surface of larger cationic liposomes thus forming multi- compartment complexes composed exclusively of natural and synthetic lipids. The complexes contained two dozen anionic liposomes per a single cationic liposome and showed low cytotoxicity and ability to enzyme-induced bio-degradation. The liposomal multi-compartment complexes demonstrate great application potential as containers for drug encapsulation and delivery.     

Photochemically and electrochemically triggered Au nanoparticles "sponges"

Stimuli-triggered wettability of surfaces and controlled uptake and release of substrates by "smart" materials are essential for drug delivery and microfluidic control. A composite "sponge" consisting of bis-aniline-bridged Au nanoparticles (NPs), functionalized with photoisomerizable nitrospiropyran/nitromerocyanine that includes selective imprinted molecular recognition sites for N,N'-bis(3-sulfonatopropyl)-4,4'-bipyridinium (PVS) was electropolymerized on a Au electrode. The system is triggered by photonic and/or electrical signals to yield four different states exhibiting variable binding/release capacities for PVS and controlled wettability of the surface. The electrical/optical uptake and release of PVS to and from the Au NPs "sponge", respectively, is followed by CdSe/ZnS quantum dots, acting as an auxiliary photonic label.     

Chip-based SALDI-MS for rapid determination of intracellular ratios of glutathione to glutathione disulfide

Alterations in the ratio of glutathione(GSH) to glutathione disulfide(GSSG) reveal the cell living state and are associated with a variety of diseases. In this study, an Au NPs grafted nanoporous silicon chip was used for surface assisted laser desorption ionization-mass spectrometry(SALDI-MS) detection of GSH. Due to the bond interaction between thiol of GSH and Au NPs modified on the chip surfaces, GSH could be captured from the complex cellular lysate. Meanwhile, the composite nanostructures of Au NPs grafted porous silicon surface presented good desorption/ionization efficiency for GSH detection. The GSH levels in different tumor cells were successfully detected. Chip-based SALDI-MS was optimized for quantification of intracellular GSH/GSSG ratio changing under drug stimulation in liver tumor cells, GSSG was reduced to GSH by reductant of tris(2-carboxyethyl)phosphine(TCEP) and isotope-labeling GSH was as an internal standard. It was found that the increasing concentration of drug irinotecan and hypoxia culture condition caused the rapid consumption of GSH and a decrease of GSH/GSSG ratio in liver tumor cells. The developed SALDI-MS method provided a convenient way to accurately measure and rapidly monitor cellular GSH value and the ratios of GSH/GSSG.     

Understanding the degradation pathway of the pesticide, chlorpyrifos by noble metal nanoparticles

Application of nanoparticles (NPs) in environmental remediation such as water purification requires a detailed understanding of the mechanistic aspects of the interaction between the species involved. Here, an attempt was made to understand the chemistry of noble metal nanoparticle-pesticide interaction, as these nanosystems are being used extensively for water purification. Our model pesticide, chlorpyrifos (CP), belonging to the organophosphorothioate group, is shown to decompose to 3,5,6-trichloro-2-pyridinol (TCP) and diethyl thiophosphate at room temperature over Ag and Au NPs, in supported and unsupported forms. The degradation products were characterized by absorption spectroscopy and electrospray ionization mass spectrometry (ESI MS). These were further confirmed by ESI tandem mass spectrometry. The interaction of CP with NP surfaces was investigated using transmission electron microscopy, energy dispersive analysis of X-rays, Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). XPS reveals no change in the oxidation state of silver after the degradation of CP. It is proposed that the degradation of CP proceeds through the formation of AgNP-S surface complex, which is confirmed by Raman spectroscopy. In this complex, the P-O bond cleaves to yield a stable aromatic species, TCP. The rate of degradation of CP increases with increase of temperature and pH. Complete degradation of 10 mL of 2 ppm CP solution is achieved in 3 h using 100 mg of supported Ag@citrate NPs on neutral alumina at room temperature at a loading of ～0.5 wt %. The effect of alumina and monolayer protection of NPs on the degradation of CP is also investigated. The rate of degradation of CP by Ag NPs is greater than that of Au NPs. The results have implications to the application of noble metal NPs for drinking water purification, as pesticide contamination is prevalent in many parts of the world. Study shows that supported Ag and Au NPs may be employed in sustainable environmental remediation, as they can be used at room temperature in aqueous solutions without the use of additional stimulus such as UV light.     

Gene Delivery into T-Cells Using Ternary Complexes of DNA,Lipofectamine, and Carboxy-Terminal Phenylalanine-Modified Dendrimers

T-cells play critical roles in various immune reactions, and genetically engineered T-cells have attracted attention for the treatment of cancer and autoimmune diseases. Previously, it is shown that a polyamidoamine dendrimer of generation 4 (G4), modified with 1,2-cyclohexanedicarboxylic anhydride (CHex) and phenylalanine (Phe) (G4-CHex-Phe), is useful for delivery into T-cells and their subsets. In this study, an efficient non-viral gene delivery system is constructed using this dendrimer. Ternary complexes are prepared using different ratios of plasmid DNA, Lipofectamine, and G4-CHex-Phe. A carboxy-terminal dendrimer lacking Phe (G3.5) is used for comparison. These complexes are characterized using agarose gel electrophoresis, dynamic light scattering, and ζpotential measurements. In Jurkat cells, the ternary complex with G4-CHex-Phe at a P/COOH ratio of 1/5 shows higher transfection activity than other complexes, such as binary and ternary complexes with G3.5, without any significant cytotoxicity. The transfection efficiency of the G4-CHex-Phe ternary complexes decreases considerably in the presence of free G4-CHex-Phe and upon altering the complex preparation method. These results suggest that G4-CHex-Phe promotes the cellular internalization of the complexes, which is useful for gene delivery into T-cells.     

Immobilized Au nanoparticles on chitosan-biguanidine modified Fe3O4 nanoparticles and investigation of its anti-human lung cancer activity

In current nanoscience bioengineered magnetic nanoparticles (NPs) have come into prominence with considerable impact. These advanced functional materials find outstanding applications in chemical science in catalysis, environmental issues, sensing etc, as well as in biology as drug delivery agent, chemical therapeutics and others. We have been prompted to architect and synthesize a novel Au NP adorned over chitosan-biguanidine polyplex modified core–shell type magnetic nanocomposite (Fe₃O₄/CS-biguanidine/Au NPs). The bioshells facilitate to protect the core ferrite NPs as well as provides stability to the synthesized Au NPs by capping. The material was characterized using different analytical techniques like Fourier Transformed Infra-Red spectroscopy (FT-IR), Inductively Coupled Plasma-Optical Emission Microscopy (ICP-OES), Field Emission Scanning Electron Microscopy (FE-SEM), Energy Dispersive X-ray spectroscopy (EDX), Transmission Electron Microscopy (TEM), Vibrating Sample Magnetometer (VSM) and X-ray Diffraction (XRD) studies. We explored the biological application of the nanocomposite in determining cytotoxicity of three adenocarcinoma cell lines (PC-14, LC-2/ad, HLC-1) through the MTT assay. The material showed very good activity by exhibiting very low % cell viability over the cell lines dose-dependently. The IC50 of Fe₃O₄/CS-biguanidine/Au NPs were observed 503, 398 and 475 µg/mL respectively against the three cell lines. The best output was observed at a concentration of 1000 µg/mL of catalyst in terms of cytotoxicity and inhibition of lung cancer growth. The anti-cancer potential was found in close relation to their antioxidant potential.     

Biofunctionalisation of colloidal gold nanoparticles via polyelectrolytes assemblies

Bioapplications of gold nanoparticles (Au NPs) have received significant attention due to their sensitive optical characteristics which depend on particle size and shape, state of aggregation and to surrounding (bio)chemical environment. In this review, we present an overview of several methods to synthesise stable colloidal Au NPs with focus on the use of the electrostatic assembly method of polyelectrolytes (PE) to functionalise Au NPs. This versatile method allows adjusting the thickness, chemical functions and the surface charge of the shells surrounding the Au NPs, thus the relevance of these features for the bioapplications of Au NPs involving surface-mediated processes is discussed. Moreover, because the PE used can be functionalised with organic fluorophores, drugs or antibodies yielding multifunctional nanocomposites useful for those applications, this review also provides an overview of the electrostatic assembly of functionalised PE onto Au NPs and their bioapplications.     

Formation of wormlike aggregates of fluorocarbon-hydrocarbon hybrid surfactant by Langmuir-Blodgett transfer and alignment of gold nanoparticles

A novel anionic fluorocarbon-hydrocarbon hybrid surfactant (SS-Hyb-Na+) with a disulfide group has been synthesized from 11-bromo-1-undecanal and perfluorohexylethyl iodide via three steps. The Langmuir-Blodgett (LB) transfer of the 1:100 (mol/mol) mixed monolayer of SS-Hyb-Na+ and stearyl alcohol (C18OH) formed on an aqueous solution containing a cationic polymer, poly(diallyldimethylammonium chloride) (PDDA+Cl-) onto a hydrophobic silicon wafer yields the formation of wormlike aggregates consisting of SS-Hyb-/PDDA+ polyion complexes. It is found that the aggregates align along the withdrawal direction of the wafer substrate. When the wafer on which the wormlike aggregates exist is immersed into the dispersion of gold nanoparticles (Au NPs) prepared by the citrate reduction method, Au NPs align along the wormlike structures. Even though the surface of the wafer is placed either vertical or parallel to the monolayer compression direction during the LB transfer, the one-dimensional (1D) array of Au NPs is observed along the withdrawal direction of the wafer. This indicates that the wormlike aggregates of SS-Hyb-/PDDA+ complexes are aligned during the LB transfer, and the aligned aggregates behave as a scaffold in the 1D array of Au NPs.